Oxidants (Redox Reactions, including Biology)

From Wikipedia, the free encyclopedia

The two parts of a redox reaction

Rust, a slow redox reaction

A bonfire; combustion is a fast redox reaction

Sodium and fluorine bonding ionically to form sodium fluoride. Sodium loses its outer electron to give it a stable electron configuration, and this electron enters the fluorine atom exothermically. The oppositely charged ions are then attracted to each other. The sodium is oxidized, and the fluorine is reduced.

Play media

Demonstration of the reaction between a strong oxidising and a reducing agent. When few drops of glycerol (reducing agent) are added to powdered potassium permanganate (strong oxidising agent), a vigorous reaction accompanied by self-ignition starts.

Redox (short for reduction–oxidation reaction) is a chemical reaction in which the oxidation states of atoms are changed. Any such reaction involves both a reduction process and a complementary oxidation process, two key concepts involved with electron transfer processes.^[1] Redox reactions include all chemical reactions in which atoms have their oxidation state changed; in general, redox reactions involve the transfer of electrons between chemical species. The chemical species from which the electron is stripped is said to have been oxidized, while the chemical species to which the electron is added is said to have been reduced. It can be explained in simple terms:

• Oxidation is the loss of electrons or an increase in oxidation state by a molecule, atom, or ion.
• Reduction is the gain of electrons or a decrease in oxidation state by a molecule, atom, or ion.

As an example, during the combustion of wood, oxygen from the air is reduced, gaining electrons from the carbon.^[2] Although oxidation reactions are commonly associated with the formation of oxides from oxygen molecules, oxygen is not necessarily included in such reactions, as other chemical species can serve the same function.^[2]

The reaction can occur relatively slowly, as in the case of rust, or more quickly, as in the case of fire. There are simple redox processes, such as the oxidation of carbon to yield carbon dioxide (CO₂) or the reduction of carbon by hydrogen to yield methane (CH₄), and more complex processes such as the oxidation of glucose (C₆H₁₂O₆) in the human body.

Etymology

"Redox" is a portmanteau of "reduction" and "oxidation".

The word oxidation originally implied reaction with oxygen to form an oxide, since dioxygen (O₂ (g)) was historically the first recognized oxidizing agent. Later, the term was expanded to encompass oxygen-like substances that accomplished parallel chemical reactions. Ultimately, the meaning was generalized to include all processes involving loss of electrons.

The word reduction originally referred to the loss in weight upon heating a metallic ore such as a metal oxide to extract the metal. In other words, ore was "reduced" to metal. Antoine Lavoisier (1743–1794) showed that this loss of weight was due to the loss of oxygen as a gas. Later, scientists realized that the metal atom gains electrons in this process. The meaning of reduction then became generalized to include all processes involving gain of electrons. Even though "reduction" seems counter-intuitive when speaking of the gain of electrons, it might help to think of reduction as the loss of oxygen, which was its historical meaning. Since electrons are negatively charged, it is also helpful to think of this as reduction in electrical charge.

The electrochemist John Bockris has used the words electronation and deelectronation to describe reduction and oxidation processes respectively when they occur at electrodes.^[3] These words are analogous to protonation and deprotonation, but they have not been widely adopted by chemists.

The term "hydrogenation" could be used instead of reduction, since hydrogen is the reducing agent in a large number of reactions, especially in organic chemistry and biochemistry. But, unlike oxidation, which has been generalized beyond its root element, hydrogenation has maintained its specific connection to reactions that add hydrogen to another substance (e.g., the hydrogenation of unsaturated fats into saturated fats, R−CH=CH−R + H₂ → R−CH₂−CH₂−R). The word "redox" was first used in 1928.^[4]

Definitions

The processes of oxidation and reduction occur simultaneously and cannot happen independently of one another, similar to the acid–base reaction.^[2] The oxidation alone and the reduction alone are each called a half-reaction, because two half-reactions always occur together to form a whole reaction. When writing half-reactions, the gained or lost electrons are typically included explicitly in order that the half-reaction be balanced with respect to electric charge.

Though sufficient for many purposes, these general descriptions are not precisely correct. Although oxidation and reduction properly refer to a change in oxidation state — the actual transfer of electrons may never occur. The oxidation state of an atom is the fictitious charge that an atom would have if all bonds between atoms of different elements were 100% ionic. Thus, oxidation is best defined as an increase in oxidation state, and reduction as a decrease in oxidation state. In practice, the transfer of electrons will always cause a change in oxidation state, but there are many reactions that are classed as "redox" even though no electron transfer occurs (such as those involving covalent bonds).

Oxidizing and reducing agents

In redox processes, the reductant transfers electrons to the oxidant. Thus, in the reaction, the reductant or reducing agent loses electrons and is oxidized, and the oxidant or oxidizing agent gains electrons and is reduced. The pair of an oxidizing and reducing agent that are involved in a particular reaction is called a redox pair. A redox couple is a reducing species and its corresponding oxidizing form, e.g., Fe²⁺/Fe³⁺.

Oxidizers

The international pictogram for oxidizing chemicals.

Substances that have the ability to oxidize other substances (cause them to lose electrons) are said to be oxidative or oxidizing and are known as oxidizing agents, oxidants, or oxidizers. That is, the oxidant (oxidizing agent) removes electrons from another substance, and is thus itself reduced. And, because it "accepts" electrons, the oxidizing agent is also called an electron acceptor. Oxygen is the quintessential oxidizer.

Oxidants are usually chemical substances with elements in high oxidation states (e.g., H
2O
2, MnO−
4, CrO
3, Cr
2O2−
7, OsO
4), or else highly electronegative elements (O₂, F₂, Cl₂, Br₂) that can gain extra electrons by oxidizing another substance.

Reducers

Substances that have the ability to reduce other substances (cause them to gain electrons) are said to be reductive or reducing and are known as reducing agents, reductants, or reducers. The reductant (reducing agent) transfers electrons to another substance, and is thus itself oxidized. And, because it "donates" electrons, the reducing agent is also called an electron donor. Electron donors can also form charge transfer complexes with electron acceptors.

Reductants in chemistry are very diverse. Electropositive elemental metals, such as lithium, sodium, magnesium, iron, zinc, and aluminium, are good reducing agents. These metals donate or give away electrons readily. Hydride transfer reagents, such as NaBH₄ and LiAlH₄, are widely used in organic chemistry,^[5][6] primarily in the reduction of carbonyl compounds to alcohols. Another method of reduction involves the use of hydrogen gas (H₂) with a palladium, platinum, or nickel catalyst. These catalytic reductions are used primarily in the reduction of carbon-carbon double or triple bonds.

Standard electrode potentials (reduction potentials)

Each half-reaction has a standard electrode potential (E0
cell), which is equal to the potential difference or voltage at equilibrium under standard conditions of an electrochemical cell in which the cathode reaction is the half-reaction considered, and the anode is a standard hydrogen electrode where hydrogen is oxidized:

 ¹⁄₂ H₂ → H⁺ + e⁻.

The electrode potential of each half-reaction is also known as its reduction potential E0
red, or potential when the half-reaction takes place at a cathode. The reduction potential is a measure of the tendency of the oxidizing agent to be reduced. Its value is zero for H⁺ + e⁻ →  ¹⁄₂ H₂ by definition, positive for oxidizing agents stronger than H⁺ (e.g., +2.866 V for F₂) and negative for oxidizing agents that are weaker than H⁺ (e.g., −0.763 V for Zn²⁺).^[7]

For a redox reaction that takes place in a cell, the potential difference is:

E0
cell = E0
cathode – E0
anode

However, the potential of the reaction at the anode was sometimes expressed as an oxidation potential:

E0
ox = –E0
red.

The oxidation potential is a measure of the tendency of the reducing agent to be oxidized, but does not represent the physical potential at an electrode. With this notation, the cell voltage equation is written with a plus sign

E0
cell = E0
red(cathode) + E0
ox(anode)

Examples of redox reactions

Illustration of a redox reaction

A good example is the reaction between hydrogen and fluorine in which hydrogen is being oxidized and fluorine is being reduced:

H
2 + F
2 → 2 HF

We can write this overall reaction as two half-reactions:

the oxidation reaction:

H
2 → 2 H⁺ + 2 e⁻

and the reduction reaction:

F
2 + 2 e⁻ → 2 F⁻

Analyzing each half-reaction in isolation can often make the overall chemical process clearer. Because there is no net change in charge during a redox reaction, the number of electrons in excess in the oxidation reaction must equal to the number consumed by the reduction reaction (as shown above).

Elements, even in molecular form, always have an oxidation state of zero. In the first half-reaction, hydrogen is oxidized from an oxidation state of zero to an oxidation state of +1. In the second half-reaction, fluorine is reduced from an oxidation state of zero to an oxidation state of −1.

When adding the reactions together the electrons are canceled:

H 2	→	2 H+ + 2 e−
F 2 + 2 e−	→	2 F−
H2 + F2	→	2 H+ + 2 F−

And the ions combine to form hydrogen fluoride:

2 H⁺ + 2 F⁻ → 2 HF

The overall reaction is:

H
2 + F
2 → 2 HF

Metal displacement

A redox reaction is the force behind an electrochemical cell like the Galvanic cell pictured. The battery is made out of a zinc electrode in a ZnSO₄ solution connected with a wire and a porous disk to a copper electrode in a CuSO₄ solution.

In this type of reaction, a metal atom in a compound (or in a solution) is replaced by an atom of another metal. For example, copper is deposited when zinc metal is placed in a copper(II) sulfate solution:

Zn(s)+ CuSO₄(aq) → ZnSO₄(aq) + Cu(s)

In the above reaction, zinc metal displaces the copper(II) ion from copper sulfate solution and thus liberates free copper metal.

The ionic equation for this reaction is:

Zn + Cu²⁺ → Zn²⁺ + Cu

As two half-reactions, it is seen that the zinc is oxidized:

Zn → Zn²⁺ + 2 e⁻

And the copper is reduced:

Cu²⁺ + 2 e⁻ → Cu

Other examples

• The reduction of nitrate to nitrogen in the presence of an acid (denitrification):

  2 NO−
  3 + 10 e⁻ + 12 H⁺ → N₂ + 6 H₂O

• The combustion of hydrocarbons, such as in an internal combustion engine, which produces water, carbon dioxide, some partially oxidized forms such as carbon monoxide, and heat energy. Complete oxidation of materials containing carbon produces carbon dioxide.
• In organic chemistry, the stepwise oxidation of a hydrocarbon by oxygen produces water and, successively, an alcohol, an aldehyde or a ketone, a carboxylic acid, and then a peroxide.

Corrosion and rusting

Oxides, such as iron(III) oxide or rust, which consists of hydrated iron(III) oxides Fe₂O₃·nH₂O and iron(III) oxide-hydroxide (FeO(OH), Fe(OH)₃), form when oxygen combines with other elements

Iron rusting in pyrite cubes

• The term corrosion refers to the electrochemical oxidation of metals in reaction with an oxidant such as oxygen. Rusting, the formation of iron oxides, is a well-known example of electrochemical corrosion; it forms as a result of the oxidation of iron metal. Common rust often refers to iron(III) oxide, formed in the following chemical reaction:

  4 Fe + 3 O₂ → 2 Fe₂O₃

• The oxidation of iron(II) to iron(III) by hydrogen peroxide in the presence of an acid:

  Fe²⁺ → Fe³⁺ + e⁻

  H₂O₂ + 2 e⁻ → 2 OH⁻

Overall equation:

2 Fe²⁺ + H₂O₂ + 2 H⁺ → 2 Fe³⁺ + 2 H₂O

Redox reactions in industry

Cathodic protection is a technique used to control the corrosion of a metal surface by making it the cathode of an electrochemical cell. A simple method of protection connects protected metal to a more easily corroded "sacrificial anode" to act as the anode. The sacrificial metal instead of the protected metal, then, corrodes. A common application of cathodic protection is in galvanized steel, in which a sacrificial coating of zinc on steel parts protects them from rust.

The primary process of reducing ore at high temperature to produce metals is known as smelting.

Oxidation is used in a wide variety of industries such as in the production of cleaning products and oxidizing ammonia to produce nitric acid, which is used in most fertilizers.

Redox reactions are the foundation of electrochemical cells, which can generate electrical energy or support electrosynthesis.

The process of electroplating uses redox reactions to coat objects with a thin layer of a material, as in chrome-plated automotive parts, silver plating cutlery, and gold-plated jewelry.

The production of compact discs depends on a redox reaction, which coats the disc with a thin layer of metal film.^{[clarification needed]}

Redox reactions in biology

Top: ascorbic acid (reduced form of Vitamin C)
Bottom: dehydroascorbic acid (oxidized form of Vitamin C)

Many important biological processes involve redox reactions.

Cellular respiration, for instance, is the oxidation of glucose (C₆H₁₂O₆) to CO₂ and the reduction of oxygen to water. The summary equation for cell respiration is:

C₆H₁₂O₆ + 6 O₂ → 6 CO₂ + 6 H₂O

The process of cell respiration also depends heavily on the reduction of NAD⁺ to NADH and the reverse reaction (the oxidation of NADH to NAD⁺). Photosynthesis and cellular respiration are complementary, but photosynthesis is not the reverse of the redox reaction in cell respiration:

6 CO₂ + 6 H₂O + light energy → C₆H₁₂O₆ + 6 O₂

Biological energy is frequently stored and released by means of redox reactions. Photosynthesis involves the reduction of carbon dioxide into sugars and the oxidation of water into molecular oxygen. The reverse reaction, respiration, oxidizes sugars to produce carbon dioxide and water. As intermediate steps, the reduced carbon compounds are used to reduce nicotinamide adenine dinucleotide (NAD⁺), which then contributes to the creation of a proton gradient, which drives the synthesis of adenosine triphosphate (ATP) and is maintained by the reduction of oxygen. In animal cells, mitochondria perform similar functions. See the Membrane potential article.

Free radical reactions are redox reactions that occur as a part of homeostasis and killing microorganisms, where an electron detaches from a molecule and then reattaches almost instantaneously. Free radicals are a part of redox molecules and can become harmful to the human body if they do not reattach to the redox molecule or an antioxidant. Unsatisfied free radicals can spur the mutation of cells they encounter and are, thus, causes of cancer.

The term redox state is often used to describe the balance of GSH/GSSG, NAD⁺/NADH and NADP⁺/NADPH in a biological system such as a cell or organ. The redox state is reflected in the balance of several sets of metabolites (e.g., lactate and pyruvate, beta-hydroxybutyrate, and acetoacetate), whose interconversion is dependent on these ratios. An abnormal redox state can develop in a variety of deleterious situations, such as hypoxia, shock, and sepsis. Redox mechanism also control some cellular processes. Redox proteins and their genes must be co-located for redox regulation according to the CoRR hypothesis for the function of DNA in mitochondria and chloroplasts.

Redox cycling

A wide variety of aromatic compounds are enzymatically reduced to form free radicals that contain one more electron than their parent compounds. In general, the electron donor is any of a wide variety of flavoenzymes and their coenzymes. Once formed, these anion free radicals reduce molecular oxygen to superoxide, and regenerate the unchanged parent compound. The net reaction is the oxidation of the flavoenzyme's coenzymes and the reduction of molecular oxygen to form superoxide. This catalytic behavior has been described as futile cycle or redox cycling.

Examples of redox cycling-inducing molecules are the herbicide paraquat and other viologens and quinones such as menadione.^[8]

Redox reactions in geology

Mi Vida uranium mine, near Moab, Utah. The alternating red and white/green bands of sandstone correspond to oxidized and reduced conditions in groundwater redox chemistry.

In geology, redox is important to both the formation of minerals and the mobilization of minerals, and is also important in some depositional environments. In general, the redox state of most rocks can be seen in the color of the rock. The rock forms in oxidizing conditions, giving it a red color. It is then "bleached" to a green—or sometimes white—form when a reducing fluid passes through the rock. The reduced fluid can also carry uranium-bearing minerals. Famous examples of redox conditions affecting geological processes include uranium deposits and Moqui marbles.

Balancing redox reactions

Describing the overall electrochemical reaction for a redox process requires a balancing of the component half-reactions for oxidation and reduction. In general, for reactions in aqueous solution, this involves adding H⁺, OH⁻, H₂O, and electrons to compensate for the oxidation changes.

Acidic media

In acidic media, H⁺ ions and water are added to half-reactions to balance the overall reaction.
For instance, when manganese(II) reacts with sodium bismuthate:

Unbalanced reaction:	Mn2+(aq) + NaBiO3(s) → Bi3+(aq) + MnO− 4 (aq)
Oxidation:	4 H2O(l) + Mn2+(aq) → MnO− 4(aq) + 8 H+(aq) + 5 e−
Reduction:	2 e− + 6 H+ + BiO− 3(s) → Bi3+(aq) + 3 H2O(l)

The reaction is balanced by scaling the two half-cell reactions to involve the same number of electrons (multiplying the oxidation reaction by the number of electrons in the reduction step and vice versa):

8 H₂O(l) + 2 Mn²⁺(aq) → 2 MnO−
4(aq) + 16 H⁺(aq) + 10 e⁻

10 e⁻ + 30 H⁺ + 5 BiO−
3(s) → 5 Bi³⁺(aq) + 15 H₂O(l)

Adding these two reactions eliminates the electrons terms and yields the balanced reaction:

14 H⁺(aq) + 2 Mn²⁺(aq) + 5 NaBiO₃(s) → 7 H₂O(l) + 2 MnO−
4(aq) + 5 Bi³⁺(aq) + 5 Na+(aq)

Basic media

In basic media, OH⁻ ions and water are added to half reactions to balance the overall reaction.

For example, in the reaction between potassium permanganate and sodium sulfite:

Unbalanced reaction:	KMnO4 + Na2SO3 + H2O → MnO2 + Na2SO4 + KOH
Reduction:	3 e− + 2 H2O + MnO− 4 → MnO2 + 4 OH−
Oxidation:	2 OH− + SO2− 3 → SO2− 4 + H2O + 2 e−

Balancing the number of electrons in the two half-cell reactions gives:

6 e⁻ + 4 H₂O + 2 MnO−
4 → 2 MnO₂ + 8 OH⁻

6 OH⁻ + 3 SO2−
3 → 3 SO2−
4 + 3 H₂O + 6 e⁻

Adding these two half-cell reactions together gives the balanced equation:

2 KMnO₄ + 3 Na₂SO₃ + H₂O → 2 MnO₂ + 3 Na₂SO₄ + 2 KOH

Memory aids

The key terms involved in redox are often confusing to students.^[9][10] For example, an element that is oxidized loses electrons; however, that element is referred to as the reducing agent. Likewise, an element that is reduced gains electrons and is referred to as the oxidizing agent.^[11] Acronyms or mnemonics are commonly used^[12] to help remember the terminology:

• "OIL RIG" — oxidation is loss of electrons, reduction is gain of electrons.^{[9][10][11][12]}
• "LEO the lion says GER" — loss of electrons is oxidation, gain of electrons is reduction.^{[9][10][11][12]}
• "LEORA says GEROA" — loss of electrons is oxidation (reducing agent), gain of electrons is reduction (oxidizing agent).^[11]
• "RED CAT" and "AN OX", or "AnOx RedCat" ("an ox-red cat") — reduction occurs at the cathode and the anode is for oxidation.
• "RED CAT gains what AN OX loses" – reduction at the cathode gains (electrons) what anode oxidation loses (electrons).

Transcranial magnetic stimulation

From Wikipedia, the free encyclopedia

Transcranial magnetic stimulation
Intervention
Transcranial magnetic stimulation (schematic diagram)

Transcranial magnetic stimulation (TMS) is a magnetic method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator, or "coil", is placed near the head of the person receiving the treatment.^[1]:3 The coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. The coil is connected to a pulse generator, or stimulator, that delivers electric current to the coil.^[2]
TMS is used diagnostically to measure the connection between the brain and a muscle to evaluate damage from stroke, multiple sclerosis, amyotrophic lateral sclerosis, movement disorders, motor neuron disease and injuries and other disorders affecting the facial and other cranial nerves and the spinal cord.^[3]

Evidence suggests it is useful for neuropathic pain^[4] and treatment-resistant major depressive disorder.^[4][5] A 2015 Cochrane review found not enough evidence to make any conclusions in schizophrenia.^[6] For negative symptoms another review found possible efficacy.^[4] As of 2014, all other investigated uses of repetitive TMS have only possible or no clinical efficacy.^[4]

Matching the discomfort of TMS to distinguish true effects from placebo is an important and challenging issue that influences the results of clinical trials.^[4][7][8][9] The greatest risks of TMS are the rare occurrence of syncope (fainting) and even less commonly, induced seizures.^[7] Other adverse effects of TMS include discomfort or pain, transient induction of hypomania, transient cognitive changes, transient hearing loss, transient impairment of working memory, and induced currents in electrical circuits in implanted devices.^[7]

Medical uses

The use of TMS can be divided into diagnostic and therapeutic uses.

Diagnosis

TMS can be used clinically to measure activity and function of specific brain circuits in humans.^[3] The most robust and widely accepted use is in measuring the connection between the primary motor cortex and a muscle to evaluate damage from stroke, multiple sclerosis, amyotrophic lateral sclerosis, movement disorders, motor neuron disease and injuries and other disorders affecting the facial and other cranial nerves and the spinal cord.^{[3][10][11][12]} TMS has been suggested as a means of assessing short-interval intracortical inhibition (SICI) which measures the internal pathways of the motor cortex but this use has not yet been validated.^[13]

Treatment

For neuropathic pain, for which there is little effective treatment, high-frequency (HF) repetitive TMS (rTMS) appears effective.^[4] For treatment-resistant major depressive disorder, HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) appears effective and low-frequency (LF) rTMS of the right DLPFC has probable efficacy.^[4][5] The Royal Australia and New Zealand College of Psychiatrists has endorsed rTMS for treatment resistant MDD.^[14] As of October 2008, the US Food and Drug Administration authorized the use of rTMS as an effective treatment for clinical depression.^[15]

Adverse effects

Although TMS is generally regarded as safe, risks increase for therapeutic rTMS compared to single or paired TMS for diagnostic purposes.^[16] In the field of therapeutic TMS, risks increase with higher frequencies.^[7]

The greatest immediate risk is the rare occurrence of syncope (fainting) and even less commonly, induced seizures.^[7][17]

Other adverse short-term effects of TMS include discomfort or pain, transient induction of hypomania, transient cognitive changes, transient hearing loss, transient impairment of working memory, and induced currents in electrical circuits in implanted devices.^[7]

Devices and procedure

During a transcranial magnetic stimulation (TMS) procedure, a magnetic field generator, or "coil" is placed near the head of the person receiving the treatment.^[1]:3 The coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. The coil is positioned by finding anatomical landmarks on the skull including, but not limited to, the inion or the nasion.^[18] The coil is connected to a pulse generator, or stimulator, that delivers electric current to the coil.^[2]

Society and culture

Regulatory approvals

Navigated TMS

The ANT Neuro neuronavigation solution visor2 was approved as a CE class IIa medical device in April 2012.

Nexstim obtained 510(k) FDA clearance of Navigated Brain Stimulation for the assessment of the primary motor cortex for pre-procedural planning in December 2009.^[19]

Nexstim obtained FDA 510K clearance for NexSpeech navigated brain stimulation device for neurosurgical planning in June 2011.^[20]

Depression

A number of deep TMS have received FDA 510k clearance to market for use in adults with treatment resistant major depressive disorders.^{[21][22][23][24]}

Migraine

The use of single-pulse TMS was approved by the FDA for treatment of migraines in December 2013.^[25] It is approved as a Class II medical device under the "de novo pathway".^[26][27]

Health insurance

United States

Commercial health insurance

In 2013, several commercial health insurance plans in the United States, including Anthem, Health Net, and Blue Cross Blue Shield of Nebraska and of Rhode Island, covered TMS for the treatment of depression for the first time.^[28] In contrast, UnitedHealthcare issued a medical policy for TMS in 2013 that stated there is insufficient evidence that the procedure is beneficial for health outcomes in patients with depression. UnitedHealthcare noted that methodological concerns raised about the scientific evidence studying TMS for depression include small sample size, lack of a validated sham comparison in randomized controlled studies, and variable uses of outcome measures.^[29] Other commercial insurance plans whose 2013 medical coverage policies stated that the role of TMS in the treatment of depression and other disorders had not been clearly established or remained investigational included Aetna, Cigna and Regence.^[30]

Medicare

Policies for Medicare coverage vary among local jurisdictions within the Medicare system,^[31] and Medicare coverage for TMS has varied among jurisdictions and with time. For example:

• In early 2012 in New England, Medicare covered TMS for the first time in the United States.^[32] However, that jurisdiction later decided to end coverage after October, 2013.^[33]
• In August 2012, the jurisdiction covering Arkansas, Louisiana, Mississippi, Colorado, Texas, Oklahoma, and New Mexico determined that there was insufficient evidence to cover the treatment,^[34] but the same jurisdiction subsequently determined that Medicare would cover TMS for the treatment of depression after December 2013.^[35]

United Kingdom's National Health Service

The United Kingdom's National Institute for Health and Care Excellence (NICE) issues guidance to the National Health Service (NHS) in England, Wales, Scotland and Northern Ireland. NICE guidance does not cover whether or not the NHS should fund a procedure. Local NHS bodies (primary care trusts and hospital trusts) make decisions about funding after considering the clinical effectiveness of the procedure and whether the procedure represents value for money for the NHS.^[36]
NICE evaluated TMS for severe depression (IPG 242) in 2007, and subsequently considered TMS for reassessment in January 2011 but did not change its evaluation.^[37] The Institute found that TMS is safe, but there is insufficient evidence for its efficacy.^[37]

In January 2014, NICE reported the results of an evaluation of TMS for treating and preventing migraine (IPG 477). NICE found that short-term TMS is safe but there is insufficient evidence to evaluate safety for long-term and frequent uses. It found that evidence on the efficacy of TMS for the treatment of migraine is limited in quantity, that evidence for the prevention of migraine is limited in both quality and quantity.^[38]

Technical information

TMS – Butterfly Coils

TMS uses electromagnetic induction to generate an electric current across the scalp and skull without physical contact. A plastic-enclosed coil of wire is held next to the skull and when activated, produces a magnetic field oriented orthogonally to the plane of the coil. The magnetic field passes unimpeded through the skin and skull, inducing an oppositely directed current in the brain that activates nearby nerve cells in much the same way as currents applied directly to the cortical surface.^[39]

The path of this current is difficult to model because the brain is irregularly shaped and electricity and magnetism are not conducted uniformly throughout its tissues. The magnetic field is about the same strength as an MRI, and the pulse generally reaches no more than 5 centimeters into the brain unless using the deep transcranial magnetic stimulation variant of TMS.^[40] Deep TMS can reach up to 6 cm into the brain to stimulate deeper layers of the motor cortex, such as that which controls leg motion.^[41]

Mechanism of action

From the Biot–Savart law
${\displaystyle \mathbf {B} ={\frac {\mu _{0}}{4\pi }}I\int _{C}{\frac {d\mathbf {l} \times \mathbf {\hat {r}} }{r^{2}}}}$ it has been shown that a current through a wire generates a magnetic field around that wire. Transcranial magnetic stimulation is achieved by quickly discharging current from a large capacitor into a coil to produce pulsed magnetic fields between 2 and 3 T.^[42] By directing the magnetic field pulse at a targeted area of the brain, one can either depolarize or hyperpolarize neurons in the brain. The magnetic flux density pulse generated by the current pulse through the coil causes an electric field as explained by the Maxwell-Faraday equation,
${\displaystyle \nabla \times \mathbf {E} =-{\frac {\partial \mathbf {B} }{\partial t}}}$ . This electric field causes a change in the transmembrane current of the neuron, which leads to the depolarization or hyperpolarization of the neuron and the firing of an action potential.^[42]

The exact details of how TMS functions are still being explored. The effects of TMS can be divided into two types depending on the mode of stimulation:

• Single or paired pulse TMS causes neurons in the neocortex under the site of stimulation to depolarize and discharge an action potential. If used in the primary motor cortex, it produces muscle activity referred to as a motor evoked potential (MEP) which can be recorded on electromyography. If used on the occipital cortex, 'phosphenes' (flashes of light) might be perceived by the subject. In most other areas of the cortex, the participant does not consciously experience any effect, but his or her behaviour may be slightly altered (e.g., slower reaction time on a cognitive task), or changes in brain activity may be detected using sensing equipment.^[43]
• Repetitive TMS produces longer-lasting effects which persist past the initial period of stimulation. rTMS can increase or decrease the excitability of the corticospinal tract depending on the intensity of stimulation, coil orientation, and frequency. The mechanism of these effects is not clear, though it is widely believed to reflect changes in synaptic efficacy akin to long-term potentiation (LTP) and long-term depression (LTD).^[44]

MRI images, recorded during TMS of the motor cortex of the brain, have been found to match very closely with PET produced by voluntary movements of the hand muscles innervated by TMS, to 5–22 mm of accuracy.^[45] The localisation of motor areas with TMS has also been seen to correlate closely to MEG^[46] and also fMRI.^[47]

Coil types

The design of transcranial magnetic stimulation coils used in either treatment or diagnostic/experimental studies may differ in a variety of ways. These differences should be considered in the interpretation of any study result, and the type of coil used should be specified in the study methods for any published reports.

The most important considerations include:

• the type of material used to construct the core of the coil
• the geometry of the coil configuration
• the biophysical characteristics of the pulse produced by the coil.

With regard to coil composition, the core material may be either a magnetically inert substrate (i.e., the so-called 'air-core' coil design), or possess a solid, ferromagnetically active material (i.e., the so-called 'solid-core' design). Solid core coil design result in a more efficient transfer of electrical energy into a magnetic field, with a substantially reduced amount of energy dissipated as heat, and so can be operated under more aggressive duty cycles often mandated in therapeutic protocols, without treatment interruption due to heat accumulation, or the use of an accessory method of cooling the coil during operation. Varying the geometric shape of the coil itself may also result in variations in the focality, shape, and depth of cortical penetration of the magnetic field. Differences in the coil substance as well as the electronic operation of the power supply to the coil may also result in variations in the biophysical characteristics of the resulting magnetic pulse (e.g., width or duration of the magnetic field pulse). All of these features should be considered when comparing results obtained from different studies, with respect to both safety and efficacy.^[48]

A number of different types of coils exist, each of which produce different magnetic field patterns. Some examples:

• round coil: the original type of TMS coil
• figure-eight coil (i.e., butterfly coil): results in a more focal pattern of activation
• double-cone coil: conforms to shape of head, useful for deeper stimulation
• four-leaf coil: for focal stimulation of peripheral nerves^[49]
• H-coil: for deep transcranial magnetic stimulation

Design variations in the shape of the TMS coils allow much deeper penetration of the brain than the standard depth of 1.5–2.5 cm. Circular crown coils, Hesed (or H-core) coils, double cone coils, and other experimental variations can induce excitation or inhibition of neurons deeper in the brain including activation of motor neurons for the cerebellum, legs and pelvic floor. Though able to penetrate deeper in the brain, they are less able to produce a focused, localized response and are relatively non-focal.^[7]

History

Early attempts at stimulation of the brain using a magnetic field included those, in 1896, of Jacques-Arsène d'Arsonval in Paris and in 1910, of Silvanus P. Thompson in London.^{[citation needed]} The principle of inductive brain stimulation with eddy currents has been noted since the 20th century^{[citation needed]}. The first successful TMS study was performed in 1985 by Anthony Barker and his colleagues at the Royal Hallamshire Hospital in Sheffield, England.^{[50][non-primary source needed]} Its earliest application demonstrated conduction of nerve impulses from the motor cortex to the spinal cord, stimulating muscle contractions in the hand. As compared to the previous method of transcranial stimulation proposed by Merton and Morton in 1980^[51]{{primary-inline} in which direct electric current was applied to the scalp, the use of electromagnets greatly reduced the discomfort of the procedure, and allowed mapping of the cerebral cortex and its connections.

Research

TMS research in animal studies is limited due to early FDA approval of TMS treatment of drug-resistant depression. Because of this, there has been no specific coils for animal models. Hence, there are limited number of TMS coils that can be used for animal studies.^[52] There are some attempts in the literature showing new coil designs for mice with an improved stimulation profile.^[53]
Areas of research include:

• rehabilitation of aphasia and motor disability after stroke,^{[4][7][11][12][54]}
• tinnitus,^[4][55]
• anxiety disorders,^[4] including panic disorder^[56] and obsessive-compulsive disorder.^[4] The most promising areas to target for OCD appear to be the orbitofrontal cortex and the supplementary motor area.^[57] Older protocols that targeted the prefrontal dorsal cortex were less successful in treating OCD.^[58]
• amyotrophic lateral sclerosis,^[4][59]
• multiple sclerosis,^[4]
• epilepsy,^[4][60]
• Alzheimer's disease,^[4]
• Parkinson's disease,^[61]
• schizophrenia,^[4][6]
• substance abuse,^[4] addiction,^[4][62] and posttraumatic stress disorder (PTSD).^[4][63]
• autism^[64]
• brain death, coma, and other persistent vegetative states.^[4]
• Functional connectivity between the cerebellum and other areas of the brain^[65]

Study blinding

It is difficult to establish a convincing form of "sham" TMS to test for placebo effects during controlled trials in conscious individuals, due to the neck pain, headache and twitching in the scalp or upper face associated with the intervention.^[4][7] "Sham" TMS manipulations can affect cerebral glucose metabolism and MEPs, which may confound results.^[66] This problem is exacerbated when using subjective measures of improvement.^[7] Placebo responses in trials of rTMS in major depression are negatively associated with refractoriness to treatment, vary among studies and can influence results.^[67]

A 2011 review found that only 13.5% of 96 randomized control studies of rTMS to the dorsolateral prefrontal cortex had reported blinding success and that, in those studies, people in real rTMS groups were significantly more likely to think that they had received real TMS, compared with those in sham rTMS groups.^[68] Depending on the research question asked and the experimental design, matching the discomfort of rTMS to distinguish true effects from placebo can be an important and challenging issue.^[4][7][8][9]